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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Copper-inducible transcription: regulation by metal- and oxidative stress-responsive pathways.

Authors: Mattie, Michael D; Freedman, Jonathan H

Published In Am J Physiol Cell Physiol, (2004 Feb)

Abstract: Although copper is an essential metal, it is capable of catalyzing the formation of reactive oxygen species that can cause intracellular oxidative damage. We investigated the hypothesis that metal- and oxidative stress-responsive signal transduction pathways mediate the cellular and molecular responses associated with copper exposure. Transient transfection assays using COS-7 cells and mouse metallothionein-I (MT-I) or rat NAD(P)H:oxidoreductase 1-based reporter genes demonstrate that copper activates transcription via metal and antioxidant response elements. Concomitant with copper exposures is a decrease in the level of total glutathione and an increase in oxidized glutathione. Depletion of glutathione, before copper exposure, increases metal- and oxidative stress-inducible transcription and cytotoxicity. Pretreatment with the reactive oxygen scavengers aspirin or vitamin E provides partial protection against copper toxicity and reduces inducible transcription. Experiments using signal transduction inhibitors and a metal transcription factor (MTF)-1 null cell line demonstrate that copper-inducible MT-I transcription is regulated by protein kinase C and mitogen-activated protein kinase signaling pathways and requires MTF-1. The results of these studies indicate that copper activates transcription through both metal- and oxidative stress-responsive signal transduction pathways.

PubMed ID: 14576086 Exiting the NIEHS site

MeSH Terms: Animals; Antioxidants/pharmacology; COS Cells; Chlorocebus aethiops; Copper/pharmacology*; DNA-Binding Proteins; Enzyme Inhibitors/pharmacology; Free Radical Scavengers/pharmacology; Genes, Reporter/genetics; Glutathione/deficiency; Glutathione/metabolism; Metallothionein/genetics; Metals/pharmacology*; Mice; Mitogen-Activated Protein Kinases/antagonists & inhibitors; NADH, NADPH Oxidoreductases/genetics; Oxidative Stress/physiology*; Protein Kinase C/antagonists & inhibitors; Rats; Response Elements/physiology; Signal Transduction/drug effects*; Signal Transduction/physiology*; Transcription Factors/physiology; Transcription, Genetic/drug effects*; Transcription, Genetic/physiology; Transfection

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